PROJECT I: Molecular Etiology of Structural Birth Defects in CdLS

Children'S Hosp Of Philadelphia, Philadelphia PA

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Abstract

Project I's long term goal is to fully characterize the genes that cause Cornelia de Lange Syndrome (CdLS) and to identify the downstream effectors of cohesin dysruption that are involved in the individual birth defects seen in constellation in CdLS. This addresses the Program's long-term goals of explaining the etiology of CdLS and how that relates to more common isolated structural birth defects. CdLS is a dominant, genetically heterogeneous, developmental disorder consisting of pleiotropic manifestations. Characteristic features include craniofacial dysmorphia, reduction defects of the upper extremities, gastroesophageal, cardiac and ophthalmologic abnormalities, growth retardation, and neurodevelopmental delay. We have shown that mutations in genes encoding structural (SMC1A and SMC3) and regulatory (NIPBL) elements of cohesin cause CdLS. Cohesin is best understood for its canonical role in regulating sister chromatid cohesion and chromosome segregation, however its' less well understood role in gene regulation appears to be the critical function disrupted in CdLS. Since identification of cohesin's role in causing CdLS, mutations in additional cohesin accessory factors (such as ESC02) have also been identified in human developmental disorders collectively termed cohesinopathies. We have shown that partial disruption of cohesin function leads to a highly conserved pattern of gene dysregulation in CdLS-derived cell lines. We hypothesize that heterozygous mutations in cohesin regulatory and structural components that result in CdLS cause a specific pattern of downstream gene dysregulation in a temporal and tissue-specific manner that in turn results in the individual birth defects seen in constellation in CdLS. Identification of the downstream effectors of cohesin dysfunction will identify genes that are critical to these individual birth defects, such as limb defects, congenital heart defects, cleft palate and gastrointestinal abnormalities. Through the 3 Specific Aims proposed in this project we will further characterize the role of cohesin in gene regulation in humans, to understand how perturbation leads to CdLS, and to identify candidate genes that are regulated by cohesin that are important for the normal development of the structures that are affected in CdLS.